This is a application to implement blood based screening for postpartum depression (PPD) using a novel epigenetic biomarker we have developed, enabling the longitudinal evaluation of PPD specific neuroimaging phenotypes in the postpartum period in individuals at risk and in matched controls. The project will take advantage of the talents of a leader in the field of women's mental health and PPD, a highly experienced DNA methylation and biomarker researcher, and an accomplished neuroimager. Through a recent cross species translational experiment investigating hippocampal epigenetic responses to estrogen and epigenomic profiling in a prospective sample of women at risk for PPD, we identified a set of epigenetic marks functionally related to modulating synaptic plasticity and capable of predicting PPD with >85% accuracy. Our results indicated that risk to PPD is mediated by an increased sensitivity to estrogen. The availability of peripheral biomarkers opens novel opportunities to perform imaging epigenetics in the PPD population. While there is some consistency across MDD and PPD specific neuroimaging phenotypes, it is unclear if these findings represent disease etiology or the state of depression and requires longitudinal study in spontaneous and previous mood disorder diagnosed cases to elucidate. The central hypothesis is that PPD risk may arise due to an altered sensitivity of the epigenetic reprogramming machinery in response to gonadal hormones and that peripherally measured epigenetic variation at these loci will be associated with longitudinally progressive depression associated neuroimaging phenotypes including resting state functional connectivity alterations of corticolimbic pathways, emotional processing, working memory, and hippocampal subregion specific activity changes in the postpartum period. In Aim 1, we will use standard third trimester blood draws to perform PPD prediction and generate a sample of women at risk for PPD from the general population and from women with a previous history of mood disorder. In Aim 2, we will perform a series of fMRI tests to assess resting state functional connectivity, emotional response, working memory, and hippocampal subregion specific alterations at both a pre-depression time point of two weeks at six weeks during major depressive episodes. A within groups comparison will identify trait associated endophenotypes that will be integrated with epigenetic, serum hormone, and psychological data in Aim 3. The analyses performed will identify novel brain endophenotypes susceptible to hormone and epigenetic interaction that will aid in our understanding of the molecular pathology of PPD and hold the potential to act as novel and modifiable therapeutic targets.